Hepatitis C virus (HCV) is the most common cause of chronic viral hepatitis in the United States. HIV coinfection and African ancestry are associated with impaired response to current standard of care pegylated IFN-alpha/ribavirin (PegIFN/RBV) and PegIFN/RBV/protease inhibitor (PI) therapy. Mechanisms underlying these associations are not clear, though IL28B (IFN-gamma3) gene region SNP genotype likely accounts for half of the racial association and HIV-associated immune impairment likely accounts for the HIV association. IL28B genotype is thought to affect level of IL28B expression, though little else is known about the mechanism of action. Newer PI containing therapy has increased HCV genotype 1 sustained virologic response (SVR) rates to around 70%. However, the need to combine PIs with PegIFN/RBV means that response to PI containing therapy remains IFN-alpha and IL28B dependent. Moreover, difficult to treat population (including HIV and African descent) PegIFN/RBV/PI SVR rates are likely <60%, requiring innovative strategies. Therefore, investigation of the mechanism underlying HIV, race and IL28B genotype effect on PegIFN/RBV/PI therapy response is key to better predict therapy outcome, and identify improved therapies. IFN-alpha has many effects on cell function, including direct natural killer (NK) cell activation. NK cell inhibitory receptor KIR2DL3 in combination with its weaker binding ligand (HLA-C1) are associated with greater clearance of acute HCV infection, and expression of specific NK cell killer immunoglobulin like receptors (KIRs) are also associated with response to IFN-alpha therapy. NK cells therefore likely play a role in control of HCV. Our new data indicate greater CD16+56- NK subset IFN-alpha R expression correlates with greater IFN-alpha induced IFN- alpha signaling, predicts response to IFN-alpha based HCV therapy, and is racially and IL28B genotype associated. Plasmacytoid dendritic cells (pDC) produce IFN-alpha during viral infection, and directly activate NK cells. Lower pDC and NK subset frequency and responsiveness to IFN are present during HIV infection. Our previous data indicate impairment in both NK and pDC contribute to impaired pDC-NK interactions in HIV infection. Lower pDC numbers and function are also present during HCV infection. Whether defects present in each infection combine in impairing HCV-HIV co-infected host ability to control of HCV is not known. Additionally, whether IL28B genotype underlies racially disparate NK IFN-alphaR expression level and consequent signaling is unclear. We propose a novel model that lends mechanistic insight into IL-28B, race and HIV effects on IFN-alpha based HCV therapy response. Elucidation of this model is intended to identify better outcome predictors, improved therapy options for difficult to treat populations, an better understand host-virus interactions. In this application we will 1) Determine the effect of IL28B, race, and HIV infection on NK and pDC-NK mediated control of HCV replication in vitro; 2) To identify the mechanism underlying HIV and HCV associated impairment in IFN dependent NK function; and 3) Determine whether IL28B associated IFN-alphaR expression and IFN-alpha dependent NK control of HCV in vitro is predictive of in vivo control of HCV during PegIFN/RBV/PI therapy for HCV in the setting of HCV and HCV-HIV infection.